Figure 1.

Drp1 loss and hAPP expression combine to impair learning and memory. A, hAPP (hAPP-J20;Drp1^wt/lox and hAPP-J20;Drp1^lox/lox) mice had significant premature mortality (∗∗p < 0.01) compared with controls (Drp1^wt/lox and Drp1^lox/lox); hAPP Drp1cKO (hAPP-J20;Drp1^lox/lox;CamKII-Cre) mice had a trend (p = 0.11) toward premature mortality compared with Drp1cKO (Drp1^lox/lox;CamKII-Cre), by log-rank Mantel–Cox test, n = 13 to 30 mice/group monitored from birth through 9 months of age. B, no weight differences were observed between genotypes up to 7 months. Data are means ± S.E.M.; n = 5-42 mice/group. C, 6–7-month-old Drp1cKO, hAPP, and hAPP Drp1cKO mice showed an increased number of total movements in an open field over the course of 15 min, as compared with controls (Drp1^wt/lox and Drp1^lox/lox). Data are means ± S.E.M.; ∗p < 0.05 by one-way ANOVA and Holm–Sidak post hoc test, n = 9–12 mice/group. D–F, both procedural and spatial learning and memory were evaluated using the Morris water maze (MWM). D, no difference in swim speeds was found throughout the 2 days of procedural learning or 7 days of spatial learning by two-way ANOVA with repeated measures, indicating that all groups had intact motor function prior to the start of spatial training. E, procedural cued training conducted on the first 2 days over six sessions (c1-6) demonstrated significant but differential learning effects between the groups. Data are means ± S.E.M.; ∗∗p < 0.01, ∗∗∗∗p < 0.0001, ˆˆp<1e-10 by average rank latency with mixed-effect modeling, n = 12–22 mice/group. F, spatial learning and memory during hidden platform training in 6–7-month-old mice. Drp1cKO and hAPP showed significant learning impairments compared with Drp1WT (control). hAPP-J20 Drp1cKO (hAPP Drp1cKO) mice showed significant learning impairments compared with hAPP-J20 (hAPP) mice. Data are means ± S.E.M.; ∗p < 0.05, ∗∗∗p < 0.001, ˆp<1e-9 by average rank latency with mixed-effect modeling, n = 12 to 22 mice/group. G and H, spatial memory was evaluated using MWM probe trials at 24 and 72 h with the hidden platform removed and measured by latency to cross the former hidden platform location (target) (G) and number of platform location (target) and nontarget (other) crossings (H). Drp1cKO, hAPP, and hAPP Drp1cKO mice showed significant memory deficits. n = 12 to 22 mice/group. Data are means ± S.E.M.; n.s. = not significant, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 by Cox proportional hazards regression models (latency to cross) and Quasi-Poisson generalized linear models (platform crossings).